title: Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice.
abstract: Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of epilepsy. Here we demonstrate that VPA is a novel activator of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism, using primary mouse and human hepatocytes. Incubation of primary mouse hepatocytes with VPA resulted in increased levels of phosphorylated AMPK and acetyl-CoA carboxylase (ACC). This finding was recapitulated using primary human hepatocytes. Pretreatment of mouse hepatocytes with a small-molecule inhibitor of AMPK, Compound C (6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine), abrogated the phosphorylation of ACC following treatment with VPA. The cytochrome P450 inhibitor 1-aminobenzotriazole blocked the VPA-stimulated phosphorylation of AMPK, suggesting a requirement for biotransformation of VPA. In line with this, treatment of hepatocytes with metabolites of VPA resulted in increased phosphorylation of AMPK/ACC as compared with VPA. Treatment of ob/ob mice with VPA for 14 days resulted in decreased liver masses, hepatic fat accumulation, and serum glucose. These results paralleled those observed in mice treated with metformin. In addition, a targeted mass spectrometry-based metabolomics assay revealed several small molecules that were differentially abundant in the serum of ob/ob mice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and its metabolites as in vitro activators of AMPK.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Avery
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects*; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D009929:Organ Size; D010084:Oxidation-Reduction; D010766:Phosphorylation; D053719:Tandem Mass Spectrometry; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase